Global Epidemiology of Drug-Induced Liver Injury (DILI)
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Current Hepatology Reports (2019) 18:274–279 https://doi.org/10.1007/s11901-019-00475-z DRUG-INDUCED LIVER INJURY (P HAYASHI, SECTION EDITOR) Global Epidemiology of Drug-Induced Liver Injury (DILI) Einar S. Björnsson1,2,3 Published online: 16 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review Drug-induced liver injury (DILI) is not an uncommon liver disease in many parts of the world. DILI is one of the most common causes of acute liver failure in most countries. The current review summarizes the global epidemiology of DILI. Recent Findings The number need to harm in terms of DILI due to amoxicillin-clavulanate was approximately 1 out 2300, but was higher for azathioprine (1 out of 133) and infliximab (1 out of 148). A retrospective Chinese study showed the highest rate of DILI in hospitalized patients with an incidence of approximately 24 patients per 100,000 annually with a more favorable prognosis in the DILI cohort than previously reported from Europe, the USA, and Asia. Summary Although large DILI registries from Europe and the USA have collected much data, more prospective studies with continual enrollment are needed particularly as new therapies such as immune modulatory and oncological medications with longer half-lives and latencies come to market. Keywords DILI . Hepatotoxicity . Epidemiology . Incidence . Prognosis . Global Introduction performed. Two in Europe and one recently in the USA are notable [13, 14, 15•]. Hepatotoxicity, drug-induced liver injury (DILI), and adverse With growing registry and cohort data, some recurring liver reactions are terms used interchangeably. For most drugs, themes are emerging. DILI from conventional and herbal idiosyncratic hepatotoxicity is a rare adverse reaction. Apart and dietary supplements (HDS) is currently one of the most from patients who participate in clinical trials who have their common causes of acute liver failure across the globe includ- liver tests monitored regularly, it is very difficult to ascertain ing Europe [4, 16], the USA [17–19], Japan [20], China [21], the true incidence of DILI. Most of the information on DILI and India [22]. Indeed, HDS-induced liver injury in the east- comes from case-control studies or retrospective cohort stud- ern part of the world has been a major problem for a long time ies [1–7]. Only a few prospective studies on DILI have been [6, 9, 12, 21], but such injury is on the rise in the west as well undertaken [8–12]. Current and ongoing studies are prospec- [23–25]. Anabolic steroids have been recognized for decades tive recruitment of cases in the Spanish Hepatotoxicity as a cause of liver injury [26••] but only recently have regis- Registry [8] and in the drug-induced liver injury network in tries put forth studies with large number of patients that can the USA [10]. Few population-based studies have been fully illustrate important clinical and genetic characteristics of this unique liver injury [27, 28•]. This article is part of the Topical Collection on Drug-Induced Liver Injury Besides HDS and anabolics, other recent publications are providing valuable and clinically useful data for individual * Einar S. Björnsson and classes of prescription medications. Perhaps most impor- [email protected] tant are recent cohort studies that describe chemotherapy and immune-modulator hepatotoxicity including multiple sclero- 1 Faculty of Medicine, University of Iceland, The National University Hospital of Iceland, Reykjavik, Iceland sis medications and anti-tumor necrosis factor (anti-TNF) agents [29–33]. A recent study has examined DILI by modern 2 Department of Internal Medicine and Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, volatile anesthetics, an important but under studied group of Reykjavik, Iceland agents [34]. In other words, growing epidemiologic data are 3 Faculty of Medicine, The National University Hospital of Iceland, filling in knowledge gaps for both overall DILI and DILI from Hringbraut, 101 Reykjavik, Iceland specific agents. The pace of publications has accelerated since Curr Hepatology Rep (2019) 18:274–279 275 the 1990s particularly from Europe, North America, and Asia. cover the spectrum of clinically relevant severity [13]. Among These data are particularly useful for the clinician as they these cases of suspected DILI, 12% required hospitalization assess the probability of DILI in their patients. and 6% died. A more recent population based study from the whole country of Iceland during a 2-year study period demonstrated Europe a slightly higher incidence of 19 cases per 100,000 per year [14]. In a total of 96 patients (56% females), DILI was caused Epidemiological research in Europe on drug-induced liver in- by a single prescription medication in 75% of the cases, by jury (DILI) took off in the early 1990s [2, 35]. These early- multiple agents in 9% and dietary supplements in 16%. The source populations were from large general practice or study most commonly implicated drugs were amoxicillin- drug databases [1, 2]. Limitations of these studies were the clavulanate (22%), diclofenac (6%), azathioprine (4%), retrospective design, making accurate diagnosis of DILI diffi- infliximab (4%), and nitrofurantoin (4%). The median dura- cult. All cohorts were selected according to their use of the tion of therapy was 20 days, and 23% were hospitalized for a study drugs. Searches were done for any liver disorder and median of 5 days (range, 2–8) and one patient died as a result case histories reviewed [1, 2]. In 2004, de Abajo et al. provid- of the liver injury [14]. Similar to other cohort studies from ed quantitative estimates on the absolute and relative risks of Europe [2–5, 8, 38], antibiotics were the most common type of acute clinically apparent DILI [2]. The strongest associations drugs leading to DILI [14]. Amoxicillin-clavulanate was the for acute DILI were seen with chlorpromazine, azathioprine, most common drug, occurring in 1 out 2350 users [6]. and sulfasalazine at approximately 1 per 1000 users. Risk of A recent hospital-based study from Germany was at odds approximately 1 per 5000 users was observed for the antiep- with previous studies identifying drugs for neurologic disor- ileptics carbamazepine and valproic acid [2]. The occurrence ders as the most commonly associated class associated with of amoxicillin-clavulanate was found to be 1 per 10,000 users DILI [39]. This study stands in distinction from other [2]. Diclofenac was the only NSAID drug associated with an European data that typically identifies antibiotics as most excess risk but was relatively lower at 1 per 15,000 users [2]. common. Another observational study among German inpa- The limitations of these studies were the retrospective design, tients suggested that selective serotonin reuptake inhibitors exclusion of over the counter drugs, and HDS products [2]. were less likely than older antidepressants to precipitate to The retrospective study design lends itself to exclusion of DILI [40]. It is unclear how much of these differences in otherwise good cases because of lack of diagnostic evaluation particular medications and classes between countries related and follow-up. Therefore, underestimation of DILI probably to true differences in risk or differences in prescribing prac- occurred. The crude incidence of DILI was found to be 2.4 tices, need, and availability. cases per 100,000 inhabitants annually [2]. As for severe liver injury from medications, antibiotics and In a retrospective single-center study from Sweden, a re- disulfiram standout in Europe. Over a 6-year study period, in markably similar incidence of 2.3/100,000 was reported [5]. tertiary referral center in Denmark, 6 patients underwent liver Among 147 patients hospitalized in the UK with elevated liver transplantation and another 9 patients died from idiosyncratic biochemistries, 13 (8.8%) were felt to be DILI cases. These 13 DILI, most often from disulfiram and antibiotics [41]. These constituted 0.7% of the 1964 admissions [35]. A study from etiologies were very similar to a Swedish study of DILI asso- Switzerland found DILI in 1.4% of hospitalized patients but ciated with a fatal outcome [4]. Furthermore, the results of the the DILI was not included among the diagnoses or in the Danish study support and document the hepatotoxicity poten- physician’s discharge letter in a high proportion of patients, tial of disulfiram [42]. highlighting the need for specific methodology that detects DILI beyond just discharge diagnoses [36]. In a population survey recruitment, 126 adult patients with DILI were pro- The USA spectively enrolled over a 9-year period, in 12 hospitals in Barcelona [37]. Drug consumption data were used to estimate DILI is the most frequent cause of acute liver failure in the the exposed population. Isoniazid, pyrazinamide, rifampicin, USA [17–19]. In a retrospective study of liver test abnormal- amoxicillin with clavulanic acid, erythromycin, chlorproma- ities in the USA from the early 1990s, drug-associated liver zine, nimesulide, and ticlopidine presented the highest DILI enzyme abnormalities were the most common cause [43]. risk [37]. However, these results have not been reproduced. In a retro- The first prospective population-based study came from spective single-center study from Michigan. Here only 32 France, and the incidence of DILI was estimated at 14 per (0.8%) of 4039 patients referred for acute and chronic liver 100,000 inhabitants per year [13]. All new cases of symptom- disease were found to have DILI [44]. Antibiotics, mostly atic DILIs were collected by general practitioners and gastro- amoxicillin/clavulanate, minocycline, nitrofurantoin, trimeth- enterologists, in order to maximize the capture of cases and oprim-sulfamethoxazole, were the class of drugs most 276 Curr Hepatology Rep (2019) 18:274–279 frequently implicated whereas amiodarone was the single The first population based study in the USA investigated agent most commonly associated with liver injury [44].